We have developed functional genomic methods to identify differentially expressed genes within focal epileptic regions of human neocortex. We discovered the induction of a small group of genes in all patients, regardless of the cause of their epilepsy. Most of these persistently-induced genes belong to a well-studied pathway used in learning and memory that includes MAP kinase signaling, immediate-early gene/transcription, and synaptic development and strengthening. These genes are extremely reliable markers of epileptic neocortex as their expression correlates precisely with interictal discharge frequency. As a means to understand their role in epilepsy, we have mapped some of these genes to specific neurons within the 6-layered human epileptic neocortex. Within these epileptic regions, we found a persistent induction of phospho-CREB and a corresponding increase in synaptic spine density. These findings generate an intriguing hypothesis that ongoing epileptic activity produces sustained MAPK signaling and gene activations that promote structural and functional changes to maintain the chronic epileptic state. The first aim in this proposal is to relate signaling intermediates in the MAPK pathway to activity-dependent gene induction and changes in synaptic organization in human epileptic neocortex. The second is to use an epileptic model in the rat to determine the functional importance of MAPK signaling on gene expression, synaptic changes, and epileptic activities so that we can develop novel human antiepileptic therapeutics.